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Regression of Intracranial Meningiomas Following Treatment with Cabozantinib

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Regression of Intracranial Meningiomas Following Treatment with Cabozantinib Case Report Regression of Intracranial Meningiomas Following Treatment with Cabozantinib Rupesh Kotecha 1,2,*, Raees Tonse 1, Haley Appel 1, Yazmin Odia 2,3 , Ritesh R. Kotecha 4 , Guilherme Rabinowits 2,5 and Minesh P. Mehta 1,2 1 Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA; [email protected] (R.T.); [email protected] (H.A.); [email protected] (M.P.M.) 2 Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; [email protected] (Y.O.); [email protected] (G.R.) 3 Department of Neuro Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA 4 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; [email protected] 5 Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA * Correspondence: [email protected]; Tel.: +1-(786)-527-8140 Abstract: Recurrent meningiomas remain a substantial treatment challenge given the lack of effective therapeutic options aside from surgery and radiation therapy, which yield limited results in the retreatment situation. Systemic therapies have little effect, and responses are rare; the search for effective systemic therapeutics remains elusive. In this case report, we provide data regarding significant responses in two radiographically diagnosed intracranial meningiomas in a patient with concurrent thyroid carcinoma treated with cabozantinib, an oral multitarget tyrosine kinase inhibitor with potent activity against MET and VEGF receptor 2. Given the clinical experience supporting the Citation: Kotecha, R.; Tonse, R.; role of VEGF agents as experimental therapeutics in meningioma and the current understanding of Appel, H.; Odia, Y.; Kotecha, R.R.; the biological pathways underlying meningioma growth, this may represent a new oral therapeutic Rabinowits, G.; Mehta, M.P. alternative, warranting prospective evaluation. Regression of Intracranial Meningiomas Following Treatment Keywords: meningioma; cabozantinib; VEGF; targeted therapy with Cabozantinib. Curr. Oncol. 2021, 28, 1537–1543. https://doi.org/ 10.3390/curroncol28020145 1. Introduction Received: 24 March 2021 Meningiomas account for approximately one-third of primary central nervous system Accepted: 15 April 2021 Published: 18 April 2021 tumors in adults. Although most meningiomas are well-differentiated, with low prolifera- tive capacity [1], recent analyses using the updated grading criteria adopted by the World Health Organization (WHO) have demonstrated that as many as 15% to 20% should be Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in classified as atypical WHO Grade II [2]. In the Radiation Therapy Oncology Group (RTOG) published maps and institutional affil- 0539, a phase II cooperative group trial assessing the safety and efficacy of risk-adapted iations. meningioma treatment strategies, “high-risk” meningioma patients (WHO grade II subto- tal resection, recurrent grade II, or any grade III), experienced a 3-year progression-free survival (PFS) of only 59%, with a 3-year local control rate of only 69% [3], prompting broad agreement for the need for more effective multimodality therapy, and the optimization of treatment strategies in this patient population. Copyright: © 2021 by the authors. Evaluation of systemic therapies in recurrent and higher grade meningiomas suggest Licensee MDPI, Basel, Switzerland. This article is an open access article that most chemotherapeutic agents have minimal to no activity against this disease group. distributed under the terms and Agents such as hydroxyurea, dacarbazine, ifosfamide, temozolomide, irinotecan, and α- conditions of the Creative Commons interferon have demonstrated no clinical efficacy [4]. The pathogenesis of meningioma is Attribution (CC BY) license (https:// incompletely understood, and studies have now focused on gene expression profiling and creativecommons.org/licenses/by/ DNA methylation arrays to characterize transcriptional and epigenetic changes in the hope 4.0/). of identifying prognostic markers and molecular drivers. Emerging data have identified Curr. Oncol. 2021, 28, 1537–1543. https://doi.org/10.3390/curroncol28020145 https://www.mdpi.com/journal/curroncol Curr. Oncol. 2021, 28 1538 the upregulation of pathways involved in growth, proliferation, and angiogenesis, includ- ing EGFR, mTOR, PDGF, and VEGF, suggesting these as potential actionable targets [5]. Moreover, high MET expression has been demonstrated to be a predictor for recurrence in meningioma [6]. Markers of angiogenesis, including increased vessel density and VEGF expression, are detectable in meningiomas, and have been linked with grade and prognosis [7,8]. At least two VEGF targeting agents have previously been tested in this setting: bevacizumab and sunitinib. Bevacizumab showed evidence of antitumor activity, including radiographic responses and prolonged PFS in a retrospective series [9]. A prospective, multi-center single-arm phase II trial investigated the efficacy of sunitinib, a small molecule tyrosine kinase inhibitor (TKI), against VEGFR and PDGFR in 36 patients with WHO grade II and III recurrent or progressive meningiomas, resulting in a very modest median PFS of 5.2 months [10]. Reports focused on recurrent WHO grade I meningiomas are limited. A phase II study evaluated the combination of bevacizumab and everolimus, an mTOR inhibitor, in patients with recurrent or progressive meningioma (n = 5 WHO grade I, 17 total) [11]. Interestingly, the median PFS was greater for WHO grade II and III tumors (22 months) as compared to grade I tumors (17 months). Similarly, another phase II study investigated the efficacy of Vatalanib, a small molecule protein kinase inhibitor with activity against VEGF receptors, PDGFR-beta, and c-kit in refractory meningiomas (n = 2 WHO grade I, 25 total), with overall modest activity [12]. Together, these studies demonstrate the promise of VEGF inhibitors in meningioma. Cabozantinib is a multitarget oral TKI with potent activity against MET and VEGF receptor 2 (VEGFR2) [13]. It is FDA-approved for the treatment of progressive metastatic medullary thyroid cancer and advanced renal cell carcinoma. In this case study, we report a patient with metastatic thyroid cancer treated with cabozantinib who demonstrated a marked response in two previously untreated, incidental intracranial meningiomas. To the best of our knowledge and based on a search of the medical literature (MEDLINE, accessed on 29 February 2020), this represents the first documented case of a response to this oral agent in meningioma and provides an encouraging example for further study. 2. Case Report A 65-year-old male with a past medical history significant for medically controlled hypertension presented initially with dysphonia and was found to have a large thyroid mass displacing the trachea and extending into the superior mediastinum. He underwent a total thyroidectomy; pathology revealed follicular thyroid carcinoma, insular variant, and he was treated with 200 mCi of oral radioactive iodine (RAI). A seven-day post-iodine scan revealed evidence of significant residual iodine-avid tissue within the thyroid bed, as well as multiple non-calcified pulmonary nodules with increased iodine uptake suspicious for bilateral metastatic pulmonary disease. He later developed symptomatic local recurrence, as well as an increase in the burden of distant metastatic disease, approximately 1 year after resection, and 9 months after RAI. He was treated with Lenvatinib 20 mg PO once daily. After a few weeks, he continued to have persistent symptoms of vocal cord paralysis and, given concern for persistent disease, underwent total laryngopharyngectomy, cervical esophagectomy, and post-operative external beam radiotherapy, and his systemic therapy was discontinued. MRIs of the spine at that time revealed a T12 metastasis with an epidural tumor treated with stereotactic body radiotherapy. At age 70, five years after initial presentation, he presented with headaches, and an MRI scan of the brain revealed a left posterior frontal parafalcine lesion measuring 2 × 1.5 × 2.5 cm, along with two stable intraventricular meningiomas (measuring approxi- mately 8.5 and 9.2 mm each). Interval brain MRI performed 2.5 months later, at the time of transfer to our center, revealed that the left parafalcine mass had increased in size to 3.5 × 3.4 × 2.4 cm, with moderate mass effect on the motor strip, with the two intraven- tricular putative meningiomas stable in size. Given the patient’s progressive weakness and lesion size, he underwent resection of the left posterior frontal parafalcine mass, and Curr. Oncol. 2021, 28, 3 2.4 cm, with moderate mass effect on the motor strip, with the two intraventricular puta- tive meningiomas stable in size. Given the patient’s progressive weakness and lesion size, Curr. Oncol. 2021, 28 1539 he underwent resection of the left posterior frontal parafalcine mass, and pathology con- firmed metastatic thyroid carcinoma consistent with his known primary. He underwent post-operative stereotactic radiosurgery to the surgical cavity and continued observation waspathology recommended confirmed for metastaticthe putative thyroid stable carcinoma meningiomas. consistent Subsequent with his restaging known primary. studies re- He underwent post-operative stereotactic radiosurgery to the surgical cavity and contin- vealed progressive metastatic
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